Key points In patients with mild heart failure with reduced ejection fraction, how does NYHA classification vary over time and how is it related to long-term prognosis? Findings In this secondary analysis of the parallel-design double-blind PARADIGM-HF trial, the NYHA classification for 8326 patients changed dynamically over time. The association between NYHA class and cardiovascular outcomes was ambiguous: while a higher NYHA classification was associated with a worse prognosis, NYHA class I patients with high natriuretic peptides had higher event rates. than patients with low natriuretic peptides of any NYHA class. Which means that NYHA class may be an incomplete predictor of adverse outcomes, and its use as a primary criterion for selecting treatment should be questioned. |
Importance
Heart failure (HF) treatment recommendations focus on the New York Heart Association (NYHA) classification, so most apparently asymptomatic patients are not eligible for disease-modifying therapies.
Goals
To evaluate within-patient variation in NYHA classification over time, the association between NYHA class and an objective measure of HF severity (N-terminal pro-B-type natriuretic peptide level [ NT-proBNP]), and its association with long-term prognosis in the PARADIGM-HF trial.
Design, environment and participants
All patients in PARADIGM-HF were in NYHA class II or higher at baseline and were treated with sacubitril-valsartan for a run-in period of 6 to 10 weeks before randomization. Patients classified as NYHA class I, II, and III in PARADIGM-HF were compared at the time of randomization.
Exhibitions
NYHA class at randomization after 6 to 10 weeks of the baseline period.
Main results and measures
The primary outcome was cardiovascular death or first hospitalization for heart failure. Logistic regression models, areas under the receiver operating characteristic curve (AUC), kernel density estimation overlays, and Cox proportional hazards models were used.
Results
The analysis included 8326 patients with known NYHA classification at the time of randomization. Of 389 patients in NYHA class I, 228 (58%) changed functional class during the first year after randomization.
NT-proBNP level was a poor discriminator of NYHA classification: for NYHA class I versus NYHA class II, the AUC was 0.51 (95% CI, 0.48-0.54 ). For NT-proBNP level, the estimated grain density overlap was 93% between NYHA class I and II, 79% between NYHA class I and III, and 83% between II and III of the NYHA.
Patients classified as NYHA III showed a clearly higher rate of cardiovascular events (NYHA III vs I, hazard ratio [HR], 1.84; 95% CI, 1.44-2.37; NYHA III vs II , HR, 1.49; 95% CI, 1.35-1.64).
Patients in NYHA class I and II revealed lower event rates (NYHA II vs I, HR, 1.24; 95% CI, 0.97-1.58). Stratification by NT-proBNP level (<1600 pg/mL or ≥1600 pg/mL) identified subgroups with distinct risk, such that NYHA class I patients with high NT-proBNP levels (n = 175) had a numerically higher event rate than patients with low NT-proBNP levels from any NYHA class (vs I, HR, 3.43; 95% CI, 2.03-5.87; vs II, HR , 2.12; 95% CI, 1.58-2.86; vs III, HR, 1.37; 95% CI, 1.00-1.88).
Conclusions and relevance
In this study, patients in NYHA class I and II had substantial overlap in objective measures and long-term prognosis.
The clinician-defined “asymptomatic” functional class masked patients who were at substantial risk for adverse outcomes. The NYHA classification could be limited in differentiating mild forms of HF.
ClinicalTrials.gov Trial Registration Identifier: NCT01035255
